Mechanisms and development of antibiotic resistance

Several reviews of the mode of action of antimycobacterial drugs and their biochemical mechanisms of resistance have been published recently (Blanchard 1996, Cole 1994, Musser 1995, Webb & Davies 1998). This information is summarized in Table 1 and Fig. 1. Briefly, for most antibiotics available for the TABLE 1 Genetics of resistance to common antimycobacterial antibiotics TABLE 1 Genetics of resistance to common antimycobacterial antibiotics indicates that uncharacterized mechanisms of...

The impact of genomics on the search for novel tuberculosis drugs

Glaxo Wellcome Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK Abstract.The emergence of multidrug-resistant strains of Mycobacterium tuberculosis has highlighted the need for new drugs to treat tuberculosis. Drugs that either shorten the overall duration of therapy or that simplify the regimen would significantly improve compliance and hence reduce treatment failure rates. The drug development process begins with identification and...

References

Abou-Zeid C, Gares M-P, Inwald J et al 1997 Induction of a type 1 immune response to a recombinant antigen from Mycobacterium tuberculosis expressed in Mycobacterium vaccae. Infect Immun 65 1856-1862 Anderson MC 1891 On Koch's treatment. Lancet i 651-652 Barnes PF, Lu S, Abrams JS, Wang E, Yamamura M, Modlin RL 1993 Cytokine production at the site of disease in tuberculosis. Infect Immun 61 3482-3489 Cohen IR 1996 Heat shock protein 60 and the regulation of autoimmunity. In van Eden W, Young DB...

The epidemiology of tuberculosis in South Africa

Early clinical descriptions oftuberculosis amongst the Black and Khoi San peoples emphasized the acute nature of the disease in those exposed to tuberculosis for the first time there was much discussion of'virgin populations' and their implications for the spread and clinical features of tuberculosis (Cummins 1929). By 1920 observers in Black rural areas considered that tuberculosis had now begun to show certain 'endemic' characteristics and was no longer so acute or extensive in its features....

General discussion II

The biosynthesis of cell wall molecules Brennan Present-day understanding of the architecture of the mycobacterial cell envelope arises from electron microscopic studies that demonstrate alternating zones of electron density and transparency reminiscent of Gram-negative cells (Brennan & Draper 1994). This evidence is in accord with chemical models of a substantial lipid permeability barrier, a staggered, pseudo-outer membrane contributed in one-half by the ca. C50 meromycolate and ca. C25...

Mechanisms for isoniazid action and resistance

Rozwarskif, James C. Sacchettini* and William R. Jacobs, Jr. Department of Microbiology and Immunology, Howard Hughes Medical Institute, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Avenue, Bronx, New York 10461, Department of Biochemistry and Biophysics, Texas A& M University, College Station, TX 77843, fDepartment of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA Abstract. Isoniazid is the most widely used...

The endocrine component

There is a further physiological correlate of the events seen in Figs 1 3. During the phase of Th1 dominance, the adrenals increase in weight, presumably because of activation of the hypothalamopituitary-adrenal axis by cytokines (see Fig. 5). However, when the response switches to Th2 the adrenals start to atrophy (Rook & Hernandez-Pando 1996). This is not an acute renal cortical necrosis but rather progressive atrophy with apoptosis. These observations have led to detailed studies of...

Environmental saprophytes the variable efficacy of BCG and the testing of new vaccines

It is important to emphasize that Figs 1 3 demonstrate that heightened susceptibility can be achieved by evoking a Th2 response to an organism that is only distantly related to M. tuberculosis, clearly indicating the crucial role of responses to 'common' antigens, probably including the stress proteins Hernandez-Pando et al 1997 . T cells that recognize these proteins constitute a major part of the T cell repertoire at birth Fischer et al 1992 . There is presumably a genetic component to the...

The choice between Thl and Th2 responses in humans nature versus nurture

Nature Nurture Human Development

Racial differences, twin and adoption studies show that host genetics contribute to susceptibility to infectious diseases such as tuberculosis. HLA-A10, -B8 and DR2 are associated with tuberculosis, whereas recently identified polymorphisms in the vitamin D receptor and mannose binding protein genes confer resistance to FIG. 1. Factors that regulate the development and effector functions of T helper Th 1 and Th2 cells. The most important factor for the induction of Th1 cells is the presence of...

The choice between Thl and Th2 responses animal models

Little is known of genetic influences on cytokine production in animals. BD10.D2 or C57BL 6 mice, which are resistant to Leishmania, have predominantly Thl responses whereas BALB c mice, which are susceptible to Leishmania, produce predominantly Th2 cytokines. The relevant locus maps to a region on chromosome 11, syntenic to human chromosome 5q31.1, a region known to control IgE levels see below Gorham et al 1996 . Cytokines exert a powerful influence on the polarization of naive T cells. Th...

The immunopathology of tuberculosis

Lung Tuberculosis Adaptation

Immunity to M. tuberculosis requires a T helper 1 Th1 pattern of response accompanied by several types of cytotoxic T cell Flynn et al 1993,1995a,b, Rook amp Hernandez-Pando 1996 . A Th2 response is disastrous even a small Th2 component exacerbates the infection in mice Lindblad et al 1997, Rook amp Hernandez-Pando 1996 . Thus, if the animals are pre-immunized so that they have a 'pure' Thl response to culture filtrate antigens of M. tuberculosis, or to the common antigens present in a...

BCG looking for order in chaos

The variable efficacy of BCG vaccines under different conditions has been discussed almost ad nauseam Bloom amp Fine 1994, Fine 1995 . In summary, we know that at least some BCG vaccines perform well, in terms of protection against pulmonary tuberculosis, under certain conditions. But the same vaccines can perform poorly in different contexts, and we remain ignorant of the determinants of this variance. Among the reasons often discussed are several that do not call immediately for genetical...